1. Field of the Invention
The present invention relates to a pharmaceutical composition comprising calcium polycarbophil which is useful for the treatment of irritable bowel syndrome (IBS) as well as the treatment of constipation and diarrhea caused by dysfunction of the lower digestive tract.
More specifically, the present invention relates to a pharmaceutical composition capable of being disintegrated in an acidic environment, comprising the widely used bulk-forming laxative and an antidiarrheic agent calcium polycarbophil.
2. Description of the Related Art
Calcium polycarbophil is the calcium salt of polyacrylic acid cross-linked with divinyl glycol (Merck Index, 11th edition, No. 1704). The specification of the U.S. Pat. No. 3,297,664 describes the use of calcium polycarbophil for the treatment of constipation and diarrhea. Some physicochemical effects, described below, are considered to participate in the mechanism of action make calcium polycarbophil effective. When calcium polycarbophil is administered orally, carboxyl groups of polyacrylic acid moiety in calcium polycarbophil are converted to free acids, by the release of calcium ions, to form free polycarbophil in the acidic environment of gastric juice. Then, the free carboxyl groups formed are ionized after the free polycarbophil is transferred to the intestines and exposed to neutral or weekly basic enteral environment. As a result, the crosslinking polymer absorbs water to form colloidal bulk. During constipation, the water-containing colloidal bulk may ease defecation by softening and bulking the feces. On the other hand, during diarrhea, it brings about an antidiarrheal effect by lowering fluidity of the intestinal water (Pharmacotherapy 2(1), 18-28, 1982). Accordingly, the release of calcium ions from calcium polycarbophil in the stomach as well as the formation of uniform dispersion of the colloidal bulk in a digestive tract play important roles in making calcium polycarbophil effective.
However, free polycarbophil with free carboxyl groups has extremely high adhesive properties, so that free polycarbophil can be used as a mucoadhesive base material for the slow release of drugs (J. Pharm. Sci., 74, 399-405, 1985). Such properties may result in the problem that medicaments containing calcium polycarbophil cannot easily be disintegrated in an aqueous acidic solution such as, for example, artificial gastric juice (about pH 1.2). More specifically, calcium polycarbophil on the surface of a medicament is converted to polycarbophil by releasing calcium ions after contact is made with an acidic solution, and then a highly adhesive layer comprising free polycarbophil is formed on the surface of the medicament, which will block the penetration of water into the inside part of the medicament and will significantly restrain the medicament from disintegrating. As a result, when a medicament comprising calcium polycarbophil is administered orally, a uniform dispersion of its ingredients cannot be formed in the digestive tract because of the failure of disintegration, which may result in insufficient clinical effect by the medicament.
A chewable tablet (trade name: Mitrolan, A. H. Robins Co., U. S.) is one of commercially available compositions comprising calcium polycarbophil, which has been developed specifically to solve above-mentioned problems. The means adapted by chewable tablet are to prepare a disintegrated composition by mastication of the medicament and then transfer the masticated composition to the stomach so as to avoid an insufficient disintegration of the medicament in the stomach. However, the medicament is hardly be acceptable to patients because of its unpleasant taste during mastication and rough and unpleasant feelings on the palate.
Japanese Patent Unexamined Publication (hereinafter referred to as JP KOKAI) No. 1988 (Sho-63)/253027, assigned to American Cyanamide Company, discloses a pharmaceutical composition in the form of tablet, which comprises calcium polycarbophil together with microcrystalline cellulose (crystalline cellulose), magnesium stearate, crosslinked polyvinyl pyrrolidone (Crospovidone), polyvinyl pyrrolidone, silica gel (silicic anhydride), and stearic acid. The tablets further comprise caramel powder and are film-coated so that patients can take the tablets easily. An example of such commercially-available such tablets is Fibercon (trade name) from Lederle Laboratory. However, the effectiveness of these tablets is found to be insufficient, since the disintegration time of these tablets is not less than 60 minutes without exception when measured by the disintegration test adopted by the Japanese Pharmacopoeia.